Amyloids are filamentous protein deposits in sizes ranging from nanometers to microns which are composed of aggregated peptide β-sheets formed from parallel or anti parallel alignments of peptide β-strands. Amyloid fibril formation has attracted a great deal of recent attention due to their association with a large number of major human diseases, including Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, Creutzfeldt-Jakob disease, prion disorders, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) and Type II diabetes (Gazit et al., Angew Chem Intl Ed., 2002, vol. 114: p. 267-269).
Quinones are compounds which include a non aromatic ring and two carbonyl groups at, e.g., the 1,4 or the 1,2 position to one another. The three basic most common quinones are benzoquinones, naphthoquinones and anthraquinones (FIG. 1).
A variety of quinones are known to act as inhibitors of various metabolic pathways in the cell, and many types of quinones are used in the field of medicinal chemistry. Both natural and designed synthetic quinones are known as antibacterial, anti-viral, and also anti-cancer agents.
WO 97/21432 discloses the use of bicylic mono- or diketone derivatives as drugs for treating inflammation, migraine and shock. WO 2006/011136 discloses naphthoquinone derivatives and their use for treating cardiovascular disease and malignancies. WO 2006/011136 relates to the use of naphthoquinone derivatives that modulate the activity of protein kinases, and use of the derivatives in pharmaceutical compositions for treating disorders associated with MAPKs signaling, ERKs signaling, p38 signaling, and JNKs signaling.
Certain quinones have been reported to reduce neurotoxicity related to β-amyloid proteins, including danthron (1,8-dihydroxyanthraquinone; Ritchie et al., 2003, Arch Neurol. vol. 60: p. 1685-1691), naphthoquinone compound selected from naturally existing juglone, 5,8-hydroxy-1,4-naphthoquinone and 1,2-naphthoquinone (JP 2007145840) and Vitamin K-type compounds (WO 03/007933 and US 2005/0107472). However, these quinones are not substituted by an amine group.
Increasing evidence supports the fundamental role of early soluble species of the beta amyloid protein (Aβ) in the pathogenesis and neurotoxicity of Alzheimer's Disease (AD). It has been established that these amyloidogenic peptides and proteins ultimately cause the synaptic lose and dementia associated with Alzheimer's Disease. While there is growing recognition that the early oligomer intermediates and not the fibrils are the most toxic amyloid forms, the molecular mechanism underlying the misfolding and assembly of amyloid proteins is not fully understood. Since these structures self-assemble from monomers into higher oligomeric or fibrillar structures in a highly ordered and efficient manner, it is likely that specific molecular recognition elements mediate this process.
Nowhere in the background art was it taught or suggested that 3-amino-1,4-naphthoquinones could serve as inhibitors of the process of formation of beta amyloid oligomers and fibrils (Aβ). There is an unmet medical need for small non-toxic organic molecules capable of penetrating the central nervous system and preventing oligomerization of beta amyloid and other amyloid type proteins involved in neurological diseases and subsequent pathological fibril formation.